The Origin of AIDS

The Acquired Immune Deficiency Syndrome is a frightening new disease entity which has sprung, in five years, from obscurity to a major worldwide epidemic with a ^HO estimate of 35000 cases worldwide, and extrapola-hons of antibody seropositivity rates suggest there to be between 1.5 and 2.5 million carriers in the USA and that 1% of the entire population of the African continent may affected. The trend has been for an exponential inCrease in the number of individuals getting the disease ^'9-1); a trend which, despite the various measures taken to counter the threat, seems unlikely to change in *he near future. The disease has already overtaken homi-C|de, suicide, accidents, and cancer as the most costly Cause of loss of years of potential life, in Manhattan and ^an Francisco,1 and it is a disease with one of the highest Case fatality rates of any infectious disease of man. Despite its recent arrival on the scene, the wheels of jhe scientific community are racing, with papers and Otters published in almost every issue of the major Scientific and medical journals, and the disease is the Object of daily press coverage and major government ^source allocation. Yet there are some who would say ^at this is too little and too late, and it is certain that the Sl9nificance of the disease was slow to be recognized, Possible because of prejudicial attitudes to those populates first to be affected homosexuals, intravenous abuses etc. It was only in the 1983 annual summary the Morbidity and Mortality Weekly Report (MMWR), that it was transferred to the 'Notifiable Disease' categ-0rV, though it is still not, in the strict sense of the word, J?tifiable, and to date there have been no reports on

J?tifiable, and to date there have been no reports on A|DS in the WHO Technical Report Series. There are three main reporting mechanisms: (1) The Centres for Disease Control (CDC) in Atlanta, Georgia, yyhich monitors the USA, and reports via the MMWR; (2) . he Communicable Disease Surveillance Centre (CDSC) London, which works with the Public Health Labora-?rV Service (PHLS), to coordinate reports from the UK; (3> The World Health Organisation (WHO) in Geneva, ^hich is responsible for coordinating reports from all ^ver the world, but which really only has accurate in-Ormation for the USA, the UK and Europe. , order for a new disease to be recognized it must ave a strikingly unusual presentation, and a cluster of Cases in a geographically well defined area, or in a ^Pecifically affected population group. AIDS had all these 6atures. In June 1981 the CDC published a report on 5 ?ases of Pneumocystis carinii pneumonia (PCP)  lather at risk groups soon became apparent. In late j 'intravenous drug abusers (IVDA) and Haitians were ^Plicated and in early 1982 the first haemophiliac AIDS cases developed. The strongest predictive factor remained promiscuity, with a history of other sexually transmitted disease as a major prognostic factor. Whether this reflected lifestyle, or implicated cofactors as important in disease expression, or simply that the presence of genital lesions allowed easier inoculation of the causative organism, was not known.
A wide range of causative factors or cofactors were considered as to their aetiological importance, for instance cytomegalovirus, or inhalation of nitrite sphincter relaxants. Speculation abounded; indeed biological warfare experimentation was a suggestion that caused intense media interest, more than once.
In any disease, in order to obtain and usefully compare information, a surveillance definition is required. That for AIDS was a purely clinical one, since the cause was, at that time, unknown. Though a characteristic pattern of immunological profile was emerging with the observation of a decrease in T4 (helper) lymphocytes, often accompanied by a rise in T8 (suppressor) cells and other signs of immunodeficiency, tests were expensive and selective testing would have biased surveillance reports.
The definition (which excluded the lymphadenopathy syndrome (LAS), AIDS related complex (ARC), prodromal or pre-AIDS, as it is variously called), demanded just two criteria the presence of a reliably diagnosed disease at least moderately predictive of cellular immune deficiency, and the absence of any known underlying cause of that immune deficiency. AIDS cases, by 6 In mid 1983, Montagnier's team at the Pasteur Institut, Paris, isolated a retrovirus from a patient with LAS, that they designated Lymphadenopathy Associated Virus (LAV).6 The next year a similar virus, denoted HTLV III, was isolated from AIDS sufferers by an American team under Gallo.7 LAV and HTLV III subsequently proved to be different isolates of the same species of virus, which is now called the Human Immunodeficiency Virus (HIV).
The isolation of the organism and the development of tests to detect antibodies in the serum of AIDS, pre-AIDS, and healthy seropositive subjects extends the range of surveillance for the disease by allowing the screening of at risk groups.
These serological tests have also allowed retrospective study of stored sera, which has shown the earliest occurrence  These threads of information and the newly emerging picture of the sheer scale of AIDS in Africa, have lead to the hypothesis that the AIDS virus originated in, and spread from Africa (Fig 2).
HIV was originally labelled Human T cell Lymphotrophic Virus III, because it was the third retrovirus (RV) discovered to infect humans, and it was similar to the type C tumourigenic RV HTLVI (isolated in 1980 from [ patients with leukaemia) and to HTLVII (isolated from a patient with hairy cell leukaemia). It has also been shown , to be related to the Lentivirinae a group of animal viruses (Fig 3). It has been variously classed on morpho-| logical grounds both as a type C, and as a type D RV, but shows features more typical of the latter.
The recognition of an Acquired Immunodeficiency Disease in non human primates ten years ago, and more recently of outbreaks of such a disease in captive macaques in US primate research centres, lead to a search for a cause of this simian AIDS or SAIDS, and the discovery of a type C Simian T Lymphotropic Virus III (STLV III).1 ?
Just as the discovery of the AIDS virus had been preceded by that of HTLV I, so the isolation of STLV I" was preceded by that of a simian tumourigenic virus, STLV I, closely related to HTLV I. STLV ill, which has also been isolated from healthy African Green Monkeys in the wild, infects a more limited range of species than STLV I and is presumed to be of more recent origin. It is similar to, but distinct from HIV (Fig 4).
Another RV, designated SAIDS-D RV, was implicated in the Washington primate research centre outbreaks of SAIDS, but was less selective in its tropisms for cells than HIV and STLV III in attacking B cells more effectively (Hl^ is highly specific for T4 lymphocytes, although it also appears to be neurotrophic).
The discovery earlier this year, of a new AIDS-causinQ virus in humans, called LAV II by Montagnier's team< may have provided a new link in the evolutionary chain of AIDS.16 This virus closely resembles STLV III, and serologically cross reacts more strongly with this than with HIV. A third virus in man, labelled HTLV IV by American discoverers, also closely resembles STLV j" and has been isolated from asymptomatic prostitutes in West Africa,17 but where the most recent isolate of an AIDS-causing virus, SBL 6669 V618 (after the State Bacteriology Laboratory), fits in remains to be seen.
This rapidly accumulating body of information would tend to suggest an ancestor AIDS virus endemic in Prl' mates, and suggests a transmission to man within the past few decades.
Research into the origin of the disease is not just an academic exercise. The discovery of SAIDS in non hu Figure 2 The Spread Of AIDS A Hypothesis. (After Daniels: AIDS Questions and Answers, p.6 1986 and others) Figure 2 The Spread Of AIDS A Hypothesis. (  The Evolution Of the AIDS Retrovirus Figure 4 The Evolution Of the AIDS Retrovirus i man primates gives us a useful animal model for the study of AIDS and its pathogenesis. The similarity of behaviour, chemistry and morphology of the viruses together with the knowledge that HIV can be experimentally innacylated into primates, and conversely, monkey viruses can be transmitted to human cells in vitro, gives us a fair idea that we can be at least reasonably confident that the model is a good one. This research is also a tool for the development of new antiviral drugs and of vaccines. The latter would be the ideal weapon in the fight against AIDS because of the fact that the virus incorporates its genome in the form of cDNA into the human T cells, and once infected, one may expect to be a persistent carrier, possibly for life. The development of vaccines would appear to be a viable proposition, since existing antibodies developed after primary infection with one strain of the AIDS virus, seem to prevent other common strains of HIV, which may differ by 20-30% of codons for the envelope gene, from subsequently infecting the same patient. An American research team have gone further, in developing an inactivated viral vaccine which successfully prevented 6 macaques from developing SAIDS, where 5 of 6 controls were viraemic, and 4 developed SAIDS on subsequent innoculation with STLV III. 19 Although HTLV IV so far has not been shown to cause disease (indeed we do not know how closely related to LAV II it is), it is unlikely that a live attenuated vaccine j would be considered to be a safe, or ethical proposition, so a human vaccine would be aimed at the viral proteins of the envelope, perhaps at the receptor protein on the virus for T cells. However, due to the variability of the codons, the vaccine would have to be directed at relatively conserved regions of the proteins. Work is going on in the genetic engineering of the Vaccinia virus, so that this could express HIV envelope proteins on its surface, in a highly immunogenic way.
Assuming that an effective vaccine could be developed, would this be the end of the story? The recent discoveries of the new disease causing organisms LAV H and SBL 6669 V6 are important in that these viruses could escape detection by the existing serological | screening tests, and that a vaccine against one virus might not protect against another.
I would like to thank Dr Sandy Macara for his encouragement and support.